Angiogenesis refers to the process of growing new blood vessels in close proximity to the existing ones. It is known that angiogenesis plays an important role in many physiological conditions, such as: embryonic development, reproduction, tissue repair and bone homeostasis. Under normal physiological mechanism, the resulting reaction can be stimulated by the promotion of angiogenic signals. For example, in the process of wound healing or menstrual cycle, there will be angiogenesis that is controllable and sustainable for about 1-2 weeks. However, pathological angiogenesis is not controllable by normal physiological mechanisms. The regulation of angiogenesis in human body plays an important homeostatic role. When angiogenesis is over progressed or expressed, it may cause obesity, psoriasis, preterm birth, endometriosis, diabetic retinopathy, age-related macular degeneration (AMD), rheumatoid arthritis and various inflammation related diseases, or acceleration of the deterioration and metastasis of tumors. In addition, when angiogenesis is insufficient, it may result in bleeding, stroke, cardiovascular disease, etc. due to defective coagulation, and even affect wound healing of patients.
In recent years, it has been found that there is a close relationship between angiogenesis and formation of tumors. When cancer cells form a tumor, the cancer cells themselves or the surrounding connective tissues will secrete angiogenic factors. These factors promote the following changes in endothelial cells: (1) decomposition and destruction of connective tissues around the tumor; (2) proliferation of endothelial cells; (3) migration of endothelial cells toward the location for the secretion of angiogenic factors; (4) re-combination of endothelial cells to form blood vessels. Angiogenesis is very important to tumor formation. When a tumor has developed to a certain size, it is necessary to generate new blood vessels for the tumor to effectively obtain nutrients and oxygen and remove waste. Angiogenesis is also important for tumor metastasis. Tumor cells must generate new blood vessels to enter the circulatory system, and then the tumor cells are transferred to other organs and tissues. After the tumor cells reach other organs and tissues, the tumor cells must generate new blood vessels in order to continue to grow in the organs and tissues. It has been confirmed that the growth or the metastasis of almost all solid tumors and vascular tumors rely on angiogenesis. Therefore, tumor formation or metastasis can be inhibited if angiogenesis can be suppressed.
Currently, there are about 19 angiogenesis inhibitors used clinically, and these drugs can be used to treat diseases including solid tumors, AMD, choroidal neovascularization, diabetic macular edema, diabetic retinopathy, ocular neoplasm, retinal venous occlusion, telangiectasis, and other related disease. Because angiogenesis is associated with a variety of diseases, the development of novel angiogenesis inhibitors is a very important research direction and development field for now and in the future.
Endothelial progenitor cells (EPCs) can be released from the bone marrow, move to ischemic tissues, and cooperate with existing blood vessels to facilitate neovascularization. EPCs are a group of cells with the ability to promote angiogenesis in the circulation, and it has been proved that late EPCs themselves can differentiate into endothelial cells, structure blood vessel formation and promote angiogenesis. Early EPCs are found to be able to release many angiogenic cytokines (such as VEGF and IL-8) to stimulate the function of peripheral endothelial cells, which in turn promote angiogenesis and vasculogenesis. Recently, it has been reported that EPCs can regulate the formation of early cancers and the subsequent cancer metastasis by activating “angiogenic switch.” Many literatures have reported that EPCs can promote neovascularization in ocular hypoxic tissues, resulting in deterioration of age-related maculopathy. These studies show that EPCs play an important role in pathological angiogenesis, and EPC-based research and development will be a promising strategy to explore anti-angiogenic agents.